Alzheimer's disease (AD) is a progressive and invariably fatal degenerative dementia and the most common form of dementia that currently affects over 5 million Americans. The quality of life and economic costs are significant with estimated U.S. health care payments of over $200 billion in 2012, plus unpaid care by over 15 million Americans that is valued at $210 billion. A noninvasive diagnosis of AD and especially at early stage is essential for effective treatment and presents an urgent unmet need. Since existing noninvasive brain imaging technologies cannot provide sufficient detail about micrometer-size changes, tissue evaluation is limited in both specificity and resolution, and the most definitive diagnosis of AD currently comes at time of autopsy. At the core of our application is the identification of amyloid-beta protein (Abeta) plaques, characteristic of AD pathology, in postmortem and live human retina of AD patients, and possibly at early stages of the disease. The discovery of Abeta plaques in postmortem retinas of AD patients was demonstrated in a study published by our Cedars-Sinai research team, which are also the founding members of NeuroVision, LLC. (NVI). Further development of a novel noninvasive retinal imaging approach by our team to detect these plaques by curcumin labeling in live AD transgenic mouse models, allowed for the in vivo imaging of Abeta plaques at unprecedented high sensitivity and specificity. The fundamental advantages of feasibility, cost and ease-of use of retinal imaging make it an attractive modality, with great potential for unequivocal early diagnosis and monitoring of AD. The principal goal of this STTR grant application is to create and validate a noninvasive retinal imaging methodology to detect Abeta deposits in the retina of AD and mild cognitive impairment patients. A major strength of this application relies on the tight collaboration between the Cedars-Sinai research group (specializing in imaging retinal AD pathology), KB Imaging Solutions LLC (image processing experts), and NeuroVision Imaging LLC (leaders in commercializing ophthalmic devices and imaging systems). It has the potential to develop, validate, and eventually commercialize a novel noninvasive retinal Abeta imaging technology to facilitate AD diagnosis, with the following specific objectives: 1) To examine the geographic location of Abeta plaques and retinal layers in the postmortem retina of AD patients so as to guide the subsequent imaging protocol; 2) To optimize the imaging device and software for curcumin fluorescence and improve signal level for the detection of Abeta plaques; and 3) To perform an initial clinical imaging study and use the data to automate the calculation of a Retinal Amyloid Index (RAI), a quantitative measure of amyloid in the retina. With the current limitations in obtaining a definitive and early diagnostic test for AD, the commercial implications of the proposed study have the potential to make a significant impact on the market.